The present invention relates to processes for resolving enantiomers contained in racemic mixtures, and more particularly, it relates to single-step methods for resolving racemic mixtures of trans-1,2-cyclobutane dicarboxylic acid utilizing a simple crystallization.
The synthesis of L-(-)-tetramisole, also known as "levamisole", is of great commercial interest because of its great activity as an anthelminthic, as disclosed in U.S. Pat. No. 3,463,786. One newly discovered process for preparing levamisole is a catalytic asymmetric synthesis through reduction of prochiral intermediates. The asymmetric reduction is achieved through catalysis by homogeneous asymmetric rhodium complexes acting on prochiral 1,4-disubstituted-4-imidazolin-2-ones. The maximum enantio-selectivity shown was a 33% enantiomeric excess attained with a catalyst system derived from (+)-DIOP (isopropylidine dihydroxy-2,3-bis(diphenylphosphino)-1,4-butene) and [Rh(COD)Cl.sub.2 ] acting on 1-(2-methoxyethyl)-3-acetyl-4-phenyl-4-imidazolin-2-one. The reduced product is converted to levamisole with retention of chirality.
Reduction of various substituted prochiral olefins using homogeneous asymmetric complexes of rhodium (I) salts as catalysts is a field that has been extensively examined in recent years. A review of the state of this art by H. B. Kagan has recently appeared in Pure and Applied Chem., 43, 401 (1976). For specific prochiral substrates the degree of enantioselectivity achieved in reduction has been found to be strongly influenced by the choice of the asymmetric tertiary phosphine derivative employed as a ligand in the catalyst complex. Different prochiral substrates have been found to require different asymmetric catalyst ligands for maximum enantioselectivity in catalytic reduction.
Exemplary of the use of bisphosphine-rhodium complexes as catalysts are the following:
U.S. Pat. No. 3,949,000 shows asymmetric diphosphines which, when reacted with rhodium-halogen salt, produces a rhodium complex. The rhodium complex is then used as a catalyst for the hydrogenation of precursors of amino acids.
Canadian Pat. No. 977,373 shows rhodium coordination complexes, containing phosphine and at least one halogen ion, wherein the optical activity of the complex resides in the phosphine ligand. These complexes are useful as catalysts in the asymmetric hydrogenation of .alpha.-amino acids using a chiral diphosphine rhodium complex as a homogeneous catalyst.
The greatest enantioselectivity has thus far been attained in the asymmetric reduction of prochiral 1,4-disubstituted-4-imidazolin-2-ones using the asymmetric cyclobutyl-diphosphine set forth in U.S. Pat. No. 3,949,000. Further, the use of the dextrorotatory isomer of the phosphine in complexation with rhodium as catalyst provides the S-1,4-disubstituted-2-imidazolidones in excess, necessary for the production of levamisole (S-2,3,5,6-tetrahydro-6-phenylimidazo-[2,1-b]-thiazole). The levorotatory isomer of the phosphine provides the undesired R isomer of the product.
The aforesaid U.S. patent shows the preparation of the d and l isomers of the asymmetric phosphine starting from the d and l isomers of the trans-1,2-cyclobutane dicarboxylic acid, respectively, and these in turn were obtained by the resolution of d,1-trans-1,2-cyclobutane dicarboxylic acid according to the procedure of Coyner and Hillman, J. Am. Chem. Soc., 71, 324 (1949).
A consideration of the literature shows two publications concerning the resolution of racemic trans-1,2-cyclobutane dicarboxylic acid, namely, L. J. Goldsworthy, J. Chem. Soc., 125, 2012 (1924) and E. C. Coyner and W. S. Hillman, J. A.m. Chem. Soc., 71, 324 (1949). Both of these prior processes utilize l-quinine as a resolving agent, and this provides 1-trans-1,2-cyclobutane dicarboxylic acid in high purity.
The d-isomer of the acid, however, could be obtained from the mother liquor only in low optical purity, and several tedious recrystallizations were necessary for obtaining the pure d-isomer of the acid. Thus, these prior art processes are impractical for obtaining the high-purity d-isomer of the cyclobutane diphosphine needed for catalytic asymmetric synthesis of levamisole.